Neocytolysis after return from high altitude (5100 m): Further evidence for absentia

Neocytolysis—selective lysis of immature red blood cells (neocytes) in response to low erythropoietin levels—is a hypothetical phenomenon that would lead to the selective removal of young red blood cells in situations of excessive red blood cell numbers. This concept was created when interpreting data on space anemia.1 The concept of neocytolysis was also applied to high altitude physiology: that is, when people return to the lowland, after prolonged sojourn at high altitude, they would need to reduce the additional red blood cells formed during the previous hypoxic stimulation.2 Data supporting the neocytolysis concept remain sparse.3 Therefore, in 2019, a prospective and controlled study was designed to test the concept of neocytolysis and to elucidate the underlying molecular regulation.4 The surprising result was, that albeit the total hemoglobin was increased in 12 volunteers staying at the Jungfraujoch Research Station (Switzerland, 3450 m) for 3 weeks and decreased after their return to Heidelberg (Germany, 105 m), no signs for neocytolysis could be found.4 This result was controversially discussed5-10 and received much attention.11 A major argument was that the altitude at the Jungfraujoch Research Station was well below the one of previous studies2, 3 and therefore did not induce neocytolysis when returning to low altitude. Thus, we repeated similar measurements as part of the study ‘Expedition 5300’ in La Rinconada, the highest city worldwide (Peru, 5100 m). ‘Expedition 5300’ aims at studying highlanders, for example chronic mountain sickness.12 In a pilot study, six volunteers (lowland-scientist involved in the study) stayed at high altitude for a total of 3 weeks, that is, 10 days in Puno (Peru, 3850 m) and 10 days in La Rinconada (5100 m), returning to Lima (Peru, sea level) and then to Grenoble and Lyon (France, approximately 250 m). The results of isotope age-cohort labeling of red blood cells after 15N-glycine ingestion are summarized in Figure 1A and compared to the control group (N = 12) of our previous Jungfraujoch study (105 m), in which we claimed the lack of neocytolysis.4 Figure 1A shows that the kinetics of the isotope appearance and disappearance in the heme of circulating erythrocytes from ‘Expedition 5300’ is very similar to the one under normoxia in Heidelberg4 and follows a Weibull distribution. There appears to be a slight delay in the appearance of 15N enrichment in circulating RBCs and the decline of the 15N enrichment in the La Rinconada study compared to sea level, but the isotope enrichment kinetics again indicates a lack of neocytolysis. Figure 1B,C report the hematocrit and the hemoglobin concentration, respectively, for the six volunteers before the ascent, at the end of the high-altitude sojourn and 2 weeks after the descent. Both parameters are significantly (p < 0.01) increased at the end of the high-altitude sojourn and again decreased significantly (p < 0.05) 2 weeks after descending. In contrast, there is no significant difference when comparing the values before ascending with the ones 2 weeks after the descent. These data support the assumption that all volunteers had an increase in total hemoglobin mass at the end of the high-altitude sojourn,4, 13 that is, the prerequisite to reduce the red blood cell number when descending. Figure 1A also shows modeled data,4 suggesting how the 15N-kinetics would look like if neocytolysis occurred. Although this pilot study within ‘Expedition 5300’ bears the limitation of only 6 volunteers and lack further supporting data, the time-course of changes in the 15N enrichment of heme isolated from the blood samples over time during and following the sojourn at 3850 and 5100 m, there is no indication of neocytolysis. This result, therefore, supports the conclusion of the study by Klein et al.4 that disproved the occurrence of neocytolysis upon descent from 3450 m altitude and upon descent from higher altitudes. Further studies on the regulation of erythropoiesis at high altitudes and red blood cell turnover after temporal (sojourn) and long-term (highlanders) hypoxic exposure followed by normoxia need to be performed to improve our understanding of red blood cell production and sequestration kinetics affecting random and senescence-dependent RBC-clearance.14 In that context, the data presented in Figure 1 are limited, but support current knowledge on the lack of neocytolysis warranting further research on this topic relevant to high-altitude medicine and the detection of anemia and polycythemia. This study was supported by the “Fonds de dotation AGIR pour les maladies chroniques” and the Air Liquide Foundation. Further funding was received from the European Framework Horizon 2020 under grant agreement number 860436 (EVIDENCE). Additionally, we acknowledge the support of Mrs. Karin Kretsch for the hemoglobin extraction/preparation. There is no conflict of interest to declare.